POSTED: May 18, 2020

Radiation, Immunotherapy + the Abscopal Effect

Dr. Charles G. Drake is the  Director of Genitourinary Oncology, Co-Director of the Cancer Immunotherapy Program, and Associate Director for Clinical Research at the Herbert Irving Comprehensive Cancer Center, New York Presbyterian/Columbia University Medical Center.  
Dr. Drake discusses the thinking behind combining radiation therapy with immunotherapy  as well as the rare but intriguing abscopal effect.

Have you had a particular patient who changed how you approach your work? 

Dr. Charles Drake: Absolutely. I had a gentleman who had metastatic, castrate-resistant prostate cancer. He had been treated with hormonal therapy. He was about to go on chemotherapy. He had progression in his bone lesions, but he developed hematuria.
On CT scan, there was a fairly clear lesion in his bladder. We couldn’t tell what it was just by the scans, and his PSA was doubling quickly, it had reached 30 or so in less than a couple of months. We sent him to Dr. Ronald Rodriguez, who was  at Johns Hopkins at the time, and he thought it looked like this was probably metastatic prostate cancer invading the gentleman’s bladder. Dr. Rodriguez did a transurethral fulguration, meaning he burned all of the tumor he could find in  the bladder. After the procedure, he told me that there was a fair amount of prostate cancer left behind. While the procedure went well, and he got most of the tumor, he didn’t get all of it.
What happened next was fascinating. The patient’s PSA dropped. His PSA  went from 30 to 20 to 10. It eventually nadired, or reached its lowest point, at less than 1 ng/ ml and he remained in remission for nearly two years. Although clearly anecdotal, in my mind, there is almost no question that this was one of those anecdotal abscopal responses, which makes you believe that it can happen. Almost certainly that was what happened for this patient. I’ll never forget it, frankly.
Interesting. An unexpected systemic response from local treatment, right?

Dr. Drake: Yes. It was brilliant. Just by treating the local disease in the bladder,
this gentleman did well for over two years before it apparently progressed again, and he wound up getting chemotherapy. He also did very well with the chemo, so in my hopeful view, that suggests that maybe this fulguration procedure sparked  a systemic immune response.
What’s the thinking behind combining radiation therapy with immunotherapy? Why take that approach?

Dr. Drake: The basic idea is that radiation, and perhaps other local modalities like cryotherapy, leads to  destruction of tumor cells. If they’re destroyed in a way that’s immunogenic or pro-immunogenic, then the dying cells are taken up by resident antigenpresenting cells. These antigenpresenting cells get activated; they traffic to the draining lymph node, if you’re lucky. If they traffic to the draining lymph nodes, and then activate a systemic immune response (T cells), then maybe you can turn a local therapy into a systemic therapy. When that happens, it’s called the abscopal effect. We can demonstrate this in mice fairly readily, but it’s quite hard to demonstrate in humans.
In the literature, it’s not that common. There’s a review paper that reports around 60 total cases in the world that are clearly documented. But if you talk to people who take care of patients, everybody has one or two that they can talk about.

Are some radiotherapy and immunotherapy combinations synergistic while some are not?

Dr. Drake: We published on this topic in collaboration with a neurosurgeon named Dr. Michael Lim. We modeled the additive effects of radiation therapy and immunotherapy first in models of glioblastoma (GBM) brain tumors in mice. We showed that anti-PD-1 was synergistic with radiation therapy in the GBM models.
In the clinic, the last time I counted, there were somewhere around 40 or more trials trying to use radiation plus anti-PD-1 to induce an abscopal response in humans. So far though, this has not yet panned out to be  a broadly applicable principle. We now think that what’s holding back an abscopal response might not be PD-1 but the presence of regulatory T cells. In the well-documented cases, two abscopal responses (one in lung cancer and one in melanoma) both occurred with anti-CTLA-4. Perhaps anti-CTLA-4 is a better partner in humans to produce
an abscopal response.
There is also a trial in kidney cancer run by Dr. Hans Hammers, my former colleague from Johns Hopkins. He’s looking at combining Yervoy (ipilimumab), Opdivo (nivolumab),  and radiation in kidney cancer. It was maybe too hopeful that we’d get a high incidence of abscopal responses when patients receive radiation plus anti-PD-1. I don’t think it’s panned out. We need to consider the regulatory T cells and maybe even some of the other suppressive elements in the tumor microenvironment.
Your group has shown that radiation therapy works by cross-presentation and not direct presentation. Can you explain what that means for patients?

Dr. Drake: Radiation does a lot of things, and one is that it makes tumors more  immunogenic; it upregulates molecules called Class I major histocompatibility complex (MHC) molecules. This would make the tumor more recognizable to the immune system. This was pretty clear across multiple tumor types. It was shown quite nicely  in prostate cancer by James Hodge at the National Institute of Health.
Radiation also does what I discussed before; it leads to the tracking of tumor antigens to the lymph nodes. In a paper we published in Cancer Immunology Research in 2015  with Dr. Andrew Sharabi as the first author, we showed that almost all of the effect was cross-presentation. That means that the tumors are presented in a draining lymph node. In some plans, you radiate the lymph nodes. But we weren’t sure if this was a good thing or a bad thing.
We recently completed a series of studies over about two years that carefully model whether it is good to radiate the lymph nodes. The answer is clear. If you radiate the lymph nodes, you ruin the combination effects of immunotherapy and radiation therapy. When combining radiation therapy with immunotherapy, you probably don’t want to radiate the lymph nodes because that’s where the antigens are presented. This paper, with Dr. Ari Mari Mariscano was recently accepted in Clinical Cancer Research . It’s a great story.

You might want to remove those surgically?

Dr. Drake: Yes, that’s true, but in the case of radiation therapy, you probably need them to present the antigen. And the mechanism is simple. When you radiate a tissue, the lymphocytes want to track there. If you radiate  a tumor, the lymphocytes also want to go to the tumor. But if you radiate the lymph node, then you kill some of the lymph node cells that are being primed, and some of the immune cells that are being primed. You also create a gradient so that the lymphocytes want to go there. When you radiate both the lymph node and the tumor, it’s like the lymphocytes get confused and can’t decide which one to choose.

Wow, that’s crazy.

Dr. Drake: I know. It’s surprising.  It could have gone one of three ways. It could have been good to radiate the lymph node; it could have been bad to radiate the lymph node;  or it could have been neutral. In our animal models, it was clearly worse if you radiate the lymph nodes.

We talk about radiation therapy as if  it’s all one thing, but do different forms of radiation therapy have different immunogenic impacts or not?

Dr. Drake: That’s a brilliant question. Even in pre-clinical models, which are  supposed to be reductionist, there is a lot of disagreement. In fact, radiation oncologists disagree vehemently. Some groups suggest that a single large dose is optimal for immunological priming. Other groups suggest that fractionated (or multiple, smaller) doses are more immunogenic than a single large dose. For example, in some models my friend and colleague Dr. Silvia Formenti has shown that maybe five fractions  are optimal.
In Dr. Sharabi’s paper, we modeled this ourselves in mice, and we thought we were going to have a definitive answer. But our results were a little equivocal; we found that fractionation didn’t seem to make that much of a difference. But it needs to be recognized that most mouse models use implants of fast-growing tumors, and we don’t quite know their relevance to human studies. In a clever Phase I trial by Regeneron, they tested their PD-1 drug in combination with two different schedules of radiation therapy. We don’t know the results yet, but the fact that they included two different doses and schedules in their Phase I shows that the field is still not quite certain about how to best combine radiation therapy with immunotherapy.
What about radiopharmaceuticals like Xofigo (radium-223)? Is that considered a form of radiation therapy?

Dr. Drake: Absolutely. Xofigo (radium- 223) emits alpha particles, and some  suggest that it’s reasonably immunogenic. Another former colleague at Johns  Hopkins—Dr. Emmanuel Antonarakis— is running a trial with Dr. Oliver Sartor combining Xofigo (radium-223) with Provenge (sipuleucel-T). They are looking into whether the vaccine effect of Provenge (sipuleucel-T)  will be amplified by killing tumor cells with the alpha particles from Xofigo (radium-223). It’s an interesting idea.  It’s also important because Xofigo (radium-223) homes beautifully to the bones, where most prostate cancer metastases occur. They may be able to prime the immune system in the bone with this strategy. It’s a clever trial that’s been open for a while. There haven’t been any preliminary results though.
It’s worth mentioning that there are other radiopharmaceuticals, too. There’s J591 anti-PSMA antibody, which has been labeled with Lutetium.
 [See page 28 to read about a clinical trial on lutetium-177 PSMA.] That might be another idea; can something like an immune checkpoint blockade or a vaccine prime or amplify local delivery of a radioisotope?

Is anyone combining those radiopharmaceuticals and checkpoint inhibitors?

Dr. Drake: In prostate cancer,  it’s a little early along. Dr. Scott Tagawa at Cornell has some of the  tools to do those combinations eventually, but they’re still getting through their Phase I and II trials  of the radiopharmaceuticals.

What else should patients know about  combining radiation with immunotherapy?

Dr. Drake: There was an article in the New England Journal of Medicine showing an abscopal response with Yervoy (ipilimumab) anti-CTLA-4  in a patient with melanoma. It was a beautifully done paper with nice immunological correlates. After that got published, we found that radiation oncologists and medical oncologists were giving people a combination of immunotherapy and radiation and were telling patients they would get abscopal responses. But that’s a bit overly ambitious. In the clinic, it’s not that easy. It’s going to be a while before we understand what’s needed therapeutically to be able to induce abscopal responses in the majority of patients. It’s going to take a little more work before we can have that happen broadly. On the other hand,  if we can make it work, it’ll be fantastic. Dr. Hammers’ trial combining antiPD-1, anti-CTLA-4, and radiation in kidney cancer is perhaps a more clever approach. That may be what we need to do.
In other words, abscopal responses  do happen, but we don’t exactly know why or how and can’t reproduce it?

Dr. Drake: Exactly. And it doesn’t happen nearly as often as we’d like.

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